Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting a large part of the elderly population. It is characterized by the presence of extracellular lesions in the brain, the amyloid plaques, and by intracellular lesions, the neurofibrillary tangles (NFT), which all contribute to the phenomena of neurodegeneration. It is known that plaques derive by the processing, so called amyloidogenic, of a larger precursor, the amyloid presursor protein (APR), whereas the NFT are composed of hyperphosphorylated protein tau. The understanding of the molecular events that lead to both plaque and tau pathology is crucial, in order to understand and foresee a possible therapeutic target for the treatment of the disease. Our lab showed that the prolyl-isomerase Pin1 could be the "molecular link" between plaque and tau pathology, since it regulates levels of phosphorylated tau and NFT formation (Liou et al., Nature 424: 556), as well as levels of phosphorylated APP and production of p-amyloid, the core of the plaque (Pastorino et al., Nature 440:528). The long-term goal of this project is to unravel the mechanisms by which Pin1 regulates the processing of APP and the production of ?-amyloid peptide, and to investigate how Pin1 could be involved in the initiation and progression of AD. APP is a large protein localized in different intracellular compartments and undergoing translocation after interacting to binding partners. The aims of this study are to investigate whether Pin1 i) affects the trafficking of APP and its functionality in cellular models, ii) may target other substrates that are involved in AD, and finally iii) whether Pin1 affects the formation and the progression of the plaques in genetically modified animal models. The relevance of this research is to pinpoint those fine molecular mechanisms that could be attractive candidate targets for the treatment of AD. The Career Development Plan here proposed is structured in order to allow the candidate to develop an independent academic research program for the study of the role of the protein Pin1 in p-amyloid pathology. The institution, Beth Israel Deaconess Medical Center at Harvard Medical School, and the close interaction with her mentor Dr. Lu are ideal conditions for the candidate to be trained in the fields of interest and to learn the skills necessary to complete her background and develop into an independent investigator.